BOSTON, Feb. 6, 2008 - ISENTRESS (raltegravir) tablets, Merck's HIV integrase inhibitor, in combination with other anti-HIV medicines, maintained significant HIV-1 viral load suppression and increased CD4 cell counts through 48 weeks of therapy compared to placebo in combination with anti-HIV medicines, in two Phase III studies of 699 treatment-experienced patients failing antiretroviral therapies (ARTs). Patients in the studies had HIV resistant to at least one drug in each of three classes [nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)] of oral antiretroviral medicines.

In October, the U.S. Food and Drug Administration (FDA) granted ISENTRESS accelerated approval for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of viral replication with HIV-1 strains resistant to multiple antiretroviral agents. The approval was based on analyses of viral load reductions and CD4 cell count increases from baseline through 24 weeks in two phase III studies of ISENTRESS. This week, 48-week data from those same studies were presented at the 15th Conference on Retroviruses and Opportunistic Infections (CROI).

The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response. The safety and efficacy of ISENTRESS have not been established in treatment-naïve adult patients or pediatric patients. There are no study results demonstrating the effect of ISENTRESS on clinical progression of HIV-1 infection.

"The 48-week efficacy results are consistent with what we observed at Week 24," said Roy Steigbigel M.D., professor of medicine, pathology, microbiology and pharmacology, State University of New York at Stony Brook and lead study investigator for one of the studies.

Isentress Studied in Nearly 700 Patients

The data presented this week are from Week 48 results from two identical ongoing multi-center, double-blind, randomized, placebo-controlled Phase III studies (BENCHMRK-1 and BENCHMRK-2) that compare ISENTRESS in combination with optimized background therapy (OBT) to placebo plus OBT. The primary endpoint of this ongoing study is the percentage of patients in each study arm that achieve HIV RNA viral levels less than 400 copies/mL at Week 16.

Patients in BENCHMRK-1 were enrolled in Europe, Asia/Pacific and Peru. The mean baseline viral load was 4.6 log10 copies/mL for the regimen with ISENTRESS and 4.5 log10 copies/mL for the placebo regimen, respectively. The median baseline CD4 cell counts were 140 cells/mm3 for the regimen with ISENTRESS and 105 cells/mm3 for the placebo regimen, respectively. Patients in BENCHMRK-2 were enrolled in North and South America. The mean baseline viral load was 4.7 log10 copies/mL for both the regimen with ISENTRESS and the placebo regimen, respectively. The median baseline CD4 cell counts were 102 cells/mm3 for the regimen with ISENTRESS and 132 cells/mm3 for the placebo regimen, respectively.

Patients who entered the study experienced treatment failure on prior antiretroviral therapies and were infected with HIV resistant to one or more drugs in each of three oral classes of ARTs (NRTIs, NNRTIs and PIs).

Patients received ISENTRESS 400 mg or placebo, each dosed orally twice daily in combination with OBT. OBT was determined based on patients' prior treatment history and results from HIV resistance testing. In order to allow for the best possible treatment regimen to be constructed for each patient, darunavir and tipranavir, which were investigational medicines in many countries at the time of this study, were allowed to be included in OBT.

Suppression of Viral Load and Increases in CD4 Cell Counts Observed through 48 Weeks

In one of these studies, called BENCHMRK-1, at 48 weeks, ISENTRESS plus OBT maintained suppression of HIV RNA levels below 400 copies/mL in 74 percent of patients (170 out of 231) compared to 36 percent of patients (43 out of 118) receiving placebo plus OBT; p<0.001.

In the companion study, BENCHMRK-2, ISENTRESS plus OBT suppressed viral loads below 400 copies/mL in 71 percent of patients (162 out of 228) compared to 38 percent of patients (45 out of 119) receiving placebo plus OBT; p<0.001.

In addition, in BENCHMRK-1, after 48 weeks of therapy, ISENTRESS plus OBT suppressed viral load to below 50 copies/mL in 65 percent of patients (149 out of 231) compared to 31 percent of patients (37 out of 118) who received placebo plus OBT; p<0.001. ISENTRESS plus OBT increased CD4 cell counts from baseline by 120 cells/mm3 compared to 49 cells/mm3 for patients receiving placebo plus OBT; p<0.001.

In BENCHMRK-2 after 48 weeks, 60 percent of patients (136 out of 228) receiving ISENTRESS plus OBT achieved viral loads below 50 copies/mL compared to 34 percent of patients (41 out of 119) receiving placebo plus OBT; p<0.001. ISENTRESS plus OBT increased CD4 cell counts from baseline by 98 cells/mm3 compared to 40 cells/mm3 for those patients receiving placebo plus OBT; p<0.001.

After 48 weeks of therapy, in BENCHMRK-1, 4 of 232 patients (1.7 percent) receiving ISENTRESS plus OBT and 4 of 118 patients (3.4 percent) receiving placebo plus OBT discontinued therapy due to adverse experiences. In addition, 7 of 232 patients (3.0 percent) receiving ISENTRESS plus OBT and 1 of 118 patients (0.8 percent) receiving placebo plus OBT experienced a serious drug-related adverse event. The most commonly reported (reported in at least two percent of patients) study therapy-related side effects in patients receiving raltegravir plus OBT were diarrhea, nausea, vomiting, fatigue, injection site pain or reaction (due to enfuvirtide), joint pain, headache and itching.

In BENCHMRK-2, 7 of 230 patients (3.0 percent) receiving ISENTRESS plus OBT and 3 of 119 patients (2.5 percent) receiving placebo plus OBT discontinued therapy. In addition, 4 of 230 patients (1.7 percent) receiving ISENTRESS plus OBT and 6 of 119 patients (5.0 percent) receiving placebo plus OBT experienced a serious drug-related adverse event.

The most commonly reported (reported in at least two percent of patients) study therapy-related side effects in patients receiving raltegravir plus OBT were bloating, abdominal pain, constipation, diarrhea, gas, nausea, vomiting, fatigue, injection site reaction (due to enfuvirtide), dizziness and headache.

"The results show that after 48 weeks ISENTRESS in combination with other anti-HIV medicines continued to provide significantly greater antiretroviral activity and increases in CD4 cells compared to placebo with other antiretroviral medicines," said David Cooper M.D., D.Sc., professor of medicine and director of the National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia.

Important Safety Information about ISENTRESS

ISENTRESS does not cure HIV or AIDS and does not prevent passing HIV to others. Healthcare providers should know that immune reconstitution syndrome has been reported in patients treated with antiretroviral therapy, which may necessitate further evaluation and treatment.

At 24 weeks, the most commonly reported adverse experiences of any severity (mild, moderate or severe) for ISENTRESS plus OBT versus placebo plus OBT, respectively, regardless of drug relationship were diarrhea (16.6 percent vs. 19.5 percent), nausea (9.9 percent vs. 14.2 percent), headache (9.7 percent vs. 11.7 percent) and fever (4..9 percent vs. 10.3 percent).

Creatine kinase elevations were observed in subjects who received SENTRESS. Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. ISENTRESS should be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medication known to cause these conditions.

Results from pooled safety analyses from three separate studies (BENCHMRK-1, BENCHMRK-2 and a Phase II dose ranging study) in treatment-experienced patients taking 400 mg of ISENTRESS dosed twice daily plus OBT or placebo plus OBT showed that after 24 weeks of therapy the rates of discontinuation of therapy due to adverse experiences were 2.0 percent in patients receiving ISENTRESS plus OBT and 1.4 percent in patients receiving placebo plus OBT.

In addition, drug-related clinical adverse events of moderate to severe intensity occurring in greater than or equal to 2.0 percent of patients were diarrhea (3.7 percent vs. 4.6 percent), nausea (2.2 percent vs. 3.2 percent) and headache (2.4 percent vs. 1.4 percent) for ISENTRESS plus OBT and placebo plus OBT, respectively.

Drug Interaction

Based on the results of drug interaction studies and the clinical trials data, no dose adjustment of ISENTRESS is required when coadministered with other antiretroviral agents. Preclinical studies showed that ISENTRESS is not metabolized by cytochrome P450 enzymes, but is primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT) 1A1; therefore, caution should be used when coadministering ISENTRESS with strong inducers of UGT 1A1 (e.g., rifampin), which may reduce plasma concentrations of ISENTRESS.

About Isentress

ISENTRESS is a single 400 mg tablet taken twice daily without regard to food. ISENTRESS does not require boosting with ritonavir.

ISENTRESS is the first medicine to be approved in a new class of antiretroviral drugs called integrase inhibitors. ISENTRESS works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. There are drugs in use that inhibit two other enzymes critical to the HIV-1 replication process - protease and reverse transcriptase - but ISENTRESS is the only drug approved that inhibits the integrase enzyme.